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This text presents the key points from the breast cancer session held during the ESMO Signalling Pathways Symposium on targeting the HER/EGFR family of receptors in breast, lung and colorectal cancer (1-2 March 2013, Sitges, Spain). Prof Martine Piccart, session moderator, summarises the key topics of the interactive discussion. Herewith, we present her talk.

Characterisation of HER-2/neu breast cancer

Prof Piccart: The first talk given by Dr Monica Arnedos from the Institut Gustave Roussy in Paris was about the characterisation of HER2-positivebreast cancer.

First of all the disease that we call HER2-positivebreast cancer clearly has very distinct anatomo-pathological and clinical features of worse prognosis, so these tumours are very often highly proliferative, poorly-differentiated. When they express hormone receptors, they express relatively low levels of hormone receptors and they have a very aggressive clinical course when they are not treated with anti-HER2 therapies.

What is also clearly emerging in the last 2 years is that this disease that we call HER2-positivebreast cancer is also heterogeneous. In particular it appears that there are major differences between the HER2-positive/ER-positive+ and the HER2-positive/ER-negativesubgroups and this can be seen in terms of gene expression profiling, for example, but also in terms of response to some anti–HER2 strategies. So just to give you an example, in the neoadjuvant trials exploring dual HER2 blockade of the HER2 receptor, that is the use of two anti-HER2 drugs, it’s very clear that the very high pathological complete responses that we have seen are mostly seen in the tumours that do not express hormone receptors.

Dr Arnedos presented a very elegant Window trial that is designed in order to perhaps identify biomarkers indicative of a strong dependence on HER2 signalling and, just for you to understand the context around this trial, in spite of 15 years of clinical use of trastuzumab, we are still unable to identify those patients who do not benefit from the drug; so the drug is essentially given to all HER2-positivepatients, while we know that probably one in two does not have this strong dependence on HER2.She explained that there are lots of efforts around the world to try and identify those biomarkers. RESPONSIFY is one example of a study that is part of a large EU grant. In the discussion, however, we all recognised that all these efforts are still very fragmented and not very likely to yield a rapid response in terms of biomarkers of sensitivity or resistance to trastuzumab. This is very worrisome, because we are now moving to the next generation of treatments where we are simply going to add drugs to trastuzumab - going in the direction of very expensive treatments and we have not identified the tumours that are really HER2 addicted, so this is a huge problem.

Furthermore she alluded to a new entity which is attracting a lot of attention today. In the HER2- breast cancer there is a small subgroup of tumours that show mutations in the HER2 receptor and that probably represents 2% of patients with breast cancer. They are typically HER2-negative, they do not show amplification of the HER2 gene. Some of these mutations have been associated to resistance to lapatinib but not to resistance to the irreversible HER TKIs, such as neratinib and afatinib, and so there are on-going trials to try to demonstrate that these tumours can respond to a small molecule, in particular these irreversible TKIs.

The hallmark of trastuzumab in the treatment of breast cancer

Prof Piccart: Dr Fatima Cardoso gave a beautiful summary of 15 years of clinical experience with trastuzumab. She started with the management of advanced HER2-positivebreast cancer. Please remember that because it is an aggressive disease, it is not so uncommon that patients present with advanced HER2-positive disease at diagnosis. So she first reminded us that you can find a discordance between the HER status of the primary tumour and the HER status of the recurrent tumour. There have been many publications on this theme and there has been a recent meta-analysis and, to make a long story short, you can expect this type of discordance in about 10% of the patients. And so what should you do when this happens? There was a consensus emerging from the advanced breast cancer conference a year and a half year ago where the experts felt that if this happens you should give the patient the targeted drug anyway; so if the tumour was HER2-negativeinitially and it becomes HER2-positiveyou should try an anti-HER2 drug and vice versa.

She demonstrated, based on a number of randomised clinical trials, that it is crucially important to start anti-HER2treatment very early on in advanced breast cancer. It’s not the kind of treatment that you can wait and give second- or third-line: the reason is that there have been trials indicating that it is only by introducing the anti-HER2 therapy early that you are going to see an impact on survival in these patients with advanced disease.

She stressed the fact that many trials use a doublet of a taxane and trastuzumab as the control arm and she stressed the fact that there are very nice data on the combination of vinorelbine and trastuzumab and she indicated that this is a very valid option as an alternative for a taxane and trastuzumab. On the other hand, at a certain point in time there were preclinical data suggesting a benefit that adding a platinum to a taxane and then adding trastuzumab would be beneficial and this has not been demonstrated in a randomised clinical trial run by the Breast Cancer Research Group (BCRG) group; so this combination is not to be recommended in clinical practice because it is toxic.

Continuing on the theme of management of advanced disease, she stressed the fact that there is a very strong suggestion that it is beneficial to continue anti-HER therapy beyond first progression; unfortunately the randomised trials that have been done to address this question are relatively small. They had big problems in recruitment, so never reached their targeted accrual and they are viewed by authorities as providing insufficient evidence and, as a result of that, in many countries continuing anti-HER2 therapy beyond first line is very difficult, almost impossible because the treatment is not being paid for.

She spoke about the benefit of dual HER2 blockade with or without chemotherapy. Essentially there are two types of dual HER2 blockade that are going to be applied soon in the practice. One is the combination of trastuzumab and lapatinib in heavily pre-treated patients: this is a chemotherapy-free combination that is quite active and that showed a survival benefit compared to lapatinib alone. On the other hand there is the first-line trial CLEOPATRA that is strongly positive, not only for progression-free survival but also for overall survival, in which patients received either a taxane, docetaxel, with the two antibodies trastuzumab and pertuzumab, or just the taxane and trastuzumab. It is a strongly positive trial but please note that because of the selection of centres participating in the study, there was a large proportion of patients in this trial who had not seen adjuvant trastuzumab, and that’s also very worrisome: it indicates that in 7 counties in the world including Europe (Eastern Europe), there are still women who do not access adjuvant trastuzumab - so the question about CLEOPATRA, of course, is: “Would the trial have be as positive as it is now if it had been run in patients who had all received adjuvant trastuzumab?”. And of course we will not have an answer to this question.

The last point Dr Cardoso made was about the unmet needs for patients developing brain metastases. In fact in HER2-positive breast cancer, there are about 40% of the patients who are going to develop brain metastases at one point in time and interestingly three-quarters of the patients will do that in the first 12 months of exposure to trastuzumab. So it’s a phenomenon that occurs quite early on and for sure it’s still a situation in the clinic where we have very unsatisfactory therapies to offer to patients. There was for a long time the belief that perhaps lapatinib would prevent the development of brain metastases, but unfortunately there was a large French study that made a head-to-head comparison between capecitabine/trastuzumab and trastuzumab plus lapatinib in patients failing first-line regimen with trastuzumab and the trial was stopped early because there was a clear superiority of the trastuzumab combination in progression-free survival and overall survival and there were very few patients developing brain metastases. So essentially this trial failed and the reason could be that to enter the trial, the patients had to have a negative brain MRI so the patients entering this trial were preselected for having a “clean” brain, and many of us feel that the trial would have been more interesting if the patients had been allowed to enter without a systematic brain MRI because in clinical practice if patients are asymptomatic we don’t perform brain MRI most of the time.

Moving now to early disease, Dr Cardoso just reminded us that there have been several very large adjuvant trials conducted, clearly demonstrating that the addition of trastuzumab to adjuvant chemotherapy, usually anthracycline/taxane-based, has a long-term impact on overall survival, interestingly in spite of crossover. So in some of the adjuvant trials, particularly in the HERA trial, more than 50% of the patients in the observation arm were offered trastuzumab and in spite of that there is still a very strong survival advantage for the trastuzumab arm at 8 years follow-up.

There was a discussion on the optimal duration of trastuzumab; the HERA trial failed to show a superiority of 2 years over 1 year. On the other hand we heard that the PHARE trial which was initiated by the French National Cancer Institute also failed to demonstrate non-inferiority of 6 months over 1 year, in spite of being a relatively large study of more than 3,300 patients.

Of course demonstrating non-inferiority is an almost impossible task and you need many more than 3,000 patients to demonstrate non-inferiority. There are other trials that are also looking at shorter duration of trastuzumab in the adjuvant setting and they will report their results in the next 2-3 years but by that time they will no longer be useful, I’m afraid, because we will probably have moved to the prescription of two anti-HER2 drugs in the adjuvant setting.

Finally, should you give trastuzumab concomitantly with chemotherapy or sequentially with chemotherapy; this is again a question for which we do not have a solid answer that statisticians can contest. Again there is a single trial in the United States that compared concomitant and sequential trastuzumab administration in the adjuvant setting and from a statistical point of view it showed a strong trend favouring the concomitant administration but it failed to reach statistical significance. Nevertheless in the breast oncology world, we all prefer the concomitant administration and we reserve the sequential administration to patients where we are worried about cardiotoxicity, like elderly patients, because the sequential administration is associated with a reduced risk of congestive heart failure.

Another message, an interesting message because it has been a highly controversial topic, is whether or not we can stop giving anthracyclines in HER2-positive breast cancer as part of adjuvant treatment.

There is only one trial which had a non-anthracycline arm. The BCRG006 trial had an arm using docetaxel and carboplatin but Dr Cardoso reminded everyone that this trial was not designed to compare these 2 arms; it was designed to show that each of the arms was better than the control. So it was not powered to compare the non- anthracycline chemotherapy regimen with the anthracycline regimen and when you look at the results they seem to be slightly inferior for the non-anthracycline arm and on the other hand the non-anthracycline arm had a better safety profile in terms of cardiotoxicity and leukaemia.

Here it looks like patients who do not have cardiac risk factors and those with a relatively high risk of relapse, all patients with positive nodes at least, should probably not be denied an anthracycline-based regimen today.

Finally Rd. Cardoso spoke briefly about a dual blockade that is currently looking very promising and that is currently being tested in large adjuvant registration trials; one of these trials will release the first results next year and the other one probably in 2015, so it’s likely our standard of care will probably change in the next 3 years.

Is there a role for personalisation between trastuzumab and lapatinib?

Prof Piccart:Dr Christoph Zielinski was given a difficult task because he has been asked to look whether there was a role for personalisation between trastuzumab and lapatinib.

So what we have to recognise is that when we have tried to challenge trastuzumab with lapatinib in randomised trials making a head-to-head comparison between these 2 drugs in breast cancer, lapatinib has always failed. So there is in metastatic disease, a first-line trial run by Canadian colleagues comparing a taxane plus trastuzumab or a taxane plus lapatinib with clear results favouring trastuzumab in terms of progression-free survival. In the CEREBEL trial, it was supposed that a lapatinib regimen would protect patients against brain metastases; it was also a trial that showed the superiority of the trastuzumab-based regimen.

On the other hand, these two drugs are different so we need to try to build on the specific characteristics of lapatinib. It is a small molecule, more prone to pass the blood brain barrier. It is perhaps less affected by the PIK3 pathway activation than trastuzumab so there are preclinical data suggesting that lapatinib also acts predominately via the MAP kinase pathway. Lapatinib is able to upregulate pro-apoptotic genes and it is also going to lead to some accumulation of membrane bound HER2 on the cell surface, so some people think that this could be an explanation why there is the synergy with trastuzumab because that could also enhance ADCC, perhaps.

So, in the future it is likely that lapatinib will have a somewhat minor role to play compared to the antibodies. It will probably still be a useful drug to be used in heavily pre-treated patients who do not want chemotherapy anymore and who can still do pretty well when you treat them with the combination of lapatinib and trastuzumab. There are some data showing that lapatinib and endocrine treatment work better than endocrine treatment alone in HER2-positive breast cancer and some patients, particularly elderly patients, simply refuse to be treated with chemotherapy.

And finally we have pretty good data showing the activity of lapatinib in the combination with capecitabine for patients with brain metastases. There was one trial which led to provocative results in France. It’s the LANDSCAPE study where patients diagnosed with minimally symptomatic brain metastases were treated with this combination and not with radiation; the trial showed that you could control the brain metastases for up to 8 months, so you could delay whole brain radiotherapy by 8 months and this was considered an interesting result especially in view of the fact that the whole brain radiotherapy induces a lot of fatigue and a lot of cognitive function problems.

Here, I summarise the way Dr Zielinski thinks lapatinib will be used in the future. What he thinks is that the dual blockade with pertuzumab/trastuzumab will become the preferred first-line regimen, T-DM1 - the drug antibody conjugate will become preferred second-line regimen and after that there will still be some room for the combination of capecitabine and lapatinib, particularly if the patients have not had a long and valuable response to a treatment that includes trastuzumab.

Adjuvant and neoadjuvant strategies in HER-2/neu disease

Prof Piccart:Dr Luca Gianni essentially gave a very nice philosophical talk showing how important neoadjuvant trials are in HER2-positive breast cancer. In this particular breast cancer subtype, the neoadjuvant trials have been extremely good at identifying the interesting new compounds for this disease, and even making a prioritisation; so he defended the concept that in the future perhaps we will run neoadjuvant trial that will establish a proof of concept that we have perhaps found a new effective treatment that the regulatory bodies will give accelerated approval for this drug or this strategy and that the adjuvant trials will then serve as confirmatory trials for this observation as well as confirmatory trials for the potential biomarkers that you will have discovered in the neoadjuvant trial. Of course, that is supposing that we will discover biomarkers in the neoadjuvant trials and up to now we have not really discovered them, but who knows…

The landscape of new anti-HER-2/neu treatments

Prof Piccart:Finally I was given the task to review the landscape of new anti-HER2 treatments and this landscape is a very interesting and rich forest with a lot of wonderful trees growing, meaning that indeed we have a lot of options for patients with HER2-positivebreast cancer in the metastatic setting and some of those options will probably then be transferred to early disease. I spoke very briefly about the second generation of HER tyrosine kinase inhibitors, afatinib, neratinib, Hsp90 inhibitors which have undergone a very slow development because the first compounds, although active, were not pursued by pharma. But I explained that there are now at least 17 Hsp inhibitors in clinical trials so it is likely that one of these drugs will be approved soon. I spoke about the results of T-DM1 which got approval by the FDA for use in advanced breast cancer and this is really the drug that medical oncologists and patients are waiting for, because it is a drug that uses the antibody trastuzumab as the “Trojan Horse”; the antibody brings the cytotoxic drug to the cancer cell because the antibody gets internalised and so the cytotoxic drug is then entering the cancer cell but not the normal cell. This drug clearly has a very interesting safety profile, and it’s now been moved to the adjuvant setting. I was a little sad to see that the registration trials in the adjuvant setting are still simply add-on trials so the patients are getting aggressive chemotherapy and trastuzumab but then on top of that they get T-DM1 so that’s, in my view, a pity because it is going to mean that a lot of money will have to be spent for this particular strategy.

Dual HER2 blockade is likely to be recognised as the new standard in adjuvant treatment of HER2-positive breast cancer in 2 to 3 years from now.

Of course in terms of resistance to even dual HER2 blockade we have a number of suspects, so the IGF pathway, the PIK3/ mTOR pathway, c-MET pathway and SRC are all potential candidates that might play a role in resistance to HER2 blockade and there are active clinical trials exploring the drugs inhibiting these pathways in patients who developed resistance.

It seems that all of us are focusing to the tumour and trying to manipulate the pathways. And maybe what is going to be the most effect strategy is not that one but the one on the other side of the river which is to manipulate the host and the microenvironment. And there are very exciting preclinical data suggesting already that you can reverse resistance to trastuzumab with anti-PD1 and anti-PD-L1 drugs, so these are agents that break immune tolerance, make the immune system work again in cancer patients, and this is an area where I am sure we’ll see exciting news in the future.